The present invention relates to a stable formulation of tranexamic acid that provides improved taste profile and a therapeutic administration of tranexamic acid.
Tranexamic acid (trans-4-aminomethyl-cyclohexanecarboxylic acid) is an antifibrinolytic agent, which is used to prevent lysis or dissolution of fibrin clots. Its mechanism of action is as a competitive inhibitor of plasminogen activation, and as a noncompetitive inhibitor of plasmin; both plasminogen and plasmin are activators of fibrinolysis and active clot-lysing agents. Tranexamic acid assists in stabilizing fibrin clots, which maintains coagulation and assists in the control of bleeding.
Tranexamic acid is commercially available as 650 mg oral tablets under the trade name LYSTEDA® from Ferring Pharmaceuticals. Tranexamic acid is also available in intravenous form under the trade name CYKLOKAPRON® from Pharmacia and Upjohn.
Tranexamic acid is used to control excess bleeding, such as heavy bleeding during menstruation (menorrhagia). Women that suffer from menorrhagia are typically treated orally with 500 mg tranexamic acid tablets, which are administered three or four times daily. The total daily dosage ranges from 3 grams/day (two tablets every eight hours) to 6 grams/day (three tablets every six hours). Unfortunately, this treatment can cause adverse gastrointestinal reactions, including nausea, vomiting, diarrhea, and cramping. It is believed these gastrointestinal side effects are due to either large dosages of tranexamic acid and/or a rapid rate of release of tranexamic acid into the stomach following administration.
Additionally tranexamic acid has a bitter taste, and prior art tranexamic acid dosage forms are reported to be difficult to consume. This results in poor patient compliance.
A further disadvantage of such tranexamic acid-containing oral dosage forms is that they are unstable and tend to discolor upon aging. Prior art formulations are known which use cyclodextrin, chelating agents or a polycarboxylic acid derivative to prevent discoloration and improve stability. However, these approaches have several drawbacks, including lack of complete taste-masking and reduced stability of the tranexamic acid.
Other proposed attempts to solve the taste and stability problems have used enteric or delayed release coatings that delay the release of the tranexamic acid until after it has passed through the low pH environment of the stomach. These delayed release formulations were developed to improve the stability of the tranexamic acid dosage form, as well as improve patient compliance due to the poor taste profile of tranexamic acid. These techniques are described in U.S. Published Application Nos. 2005/0244495; 2005/0245614 and 2005/0025825. These delayed and modified release formulations employ dual layer coating techniques that involve the application of a separate functional coating and a seal coating layer, an operation which increases the length of the manufacturing process and the cost of the product. Further, enteric coated dosage forms can result in an unnecessarily long delay in the release of the tranexamic acid, thereby decreasing the effectiveness of the tranexamic acid.
The applicants have surprisingly discovered that the combination of a controlled release core and a coating system that avoids the need to use additional coating layers, or enteric coating agents on the tranexamic acid core tablet can produce stable, therapeutic and taste-masked solid dosage forms.